Metal-free (diacetoxy)iodobenzene-mediated regioselective imidation of imidazoheterocycles using commercially available N-fluorobenzenesulfonimide as an imidating reagent has been developed. This protocol exhibits broad substrate scope with good to excellent yields of the imidated imidazopyridines under mild conditions in short reaction times. The present protocol also represents an efficient way to access the imidated derivatives of imidazo[2,1-b]thiazole, benzo[d]imidazo-[2,1-b]thiazole, indoles, and indolizines. A radical mechanistic pathway has been proposed for the present protocol.
Metal-free (diacetoxy)iodobenzene-mediated regioselective imidation of imidazoheterocycles using commercially available N-fluorobenzenesulfonimide as an imidating reagent has been developed. This protocol exhibits broad substrate scope with good to excellent yields of the imidated imidazopyridines under mild conditions in short reaction times. The present protocol also represents an efficient way to access the imidated derivatives of imidazo[2,1-b]thiazole, benzo[d]imidazo-[2,1-b]thiazole, indoles, and indolizines. A radical mechanistic pathway has been proposed for the present protocol.
Imidazopyridine, an
important class of nitrogen-containing fused
heterocyclic motif, is widely present in plant alkaloids and natural
products.[1] It is used in pharmaceutical
chemistry as well as in materials science.[2] Thus, the development of versatile methods for the synthesis and
functionalization of imidazopyridines is an important field of research
in medicinal and synthetic organicchemistry.[3,4] Over
the past decades, considerable efforts have been devoted for the incorporation
of nitrogen functionality in heterocyclic motifs because of their
wide applications in industry and pharmacology.[5] Conventionally, aromaticC–N bond formation relies
on the transition-metal-catalyzed C–N cross-coupling reactions,
such as Ullmann–Goldberg, Buchwald–Hartwig, and Chan–Lam
amination.[6] These reactions require high
temperature and prefunctionalization of starting materials. Transition-metal-catalyzed
or visible light-induced direct C–H aminations are another
efficient atom-economical coupling processes.[7,8] Direct
amination is the direct incorporation of amine or amine derivatives
to a carbon atom through the formation of C–N bond. Beside
these, one more promising strategy of direct C–N couplings
of heteroarenes with preactivated amino precursors has also been reported.[9]Over the past decade, the use of N-fluorobenzenesulfonimide
(NFSI) for the amination of aromaticC(sp2)–H bond,[10,11] alkenes or unsaturated ketones,[12] and
benzylic or allylicC–H bond[13] has
been intensely studied by using Pd and Cucatalysts. NFSIcan act
as a source of both fluoroniumcation for fluorination and nucleophilicnitrogen or nitrogen radical for amination.[14] So far, few groups have explored the transition-metal-catalyzed
amination of arenes with NFSI (Scheme a).[10] Recently, Pan and
co-workers described a copper-catalyzed imidation of heterocycles
such as thiophene, furan, and pyrrole with NFSI (Scheme b).[11] Despite these successes, the imidation of other biologically relevant
heterocycles using NFSI under metal-free mild conditions still remains
an interesting and challenging subject for researchers.
Scheme 1
Direct
Amination of Aromatic C–H Bond Using NFSI
Hypervalent iodines(III) are useful oxidants
in various coupling
reactions.[15] Moreover, iodine(III)-mediated
intramolecular and intermolecular oxidative aminations have also been
explored to construct diverse heterocycliccompounds.[16,17] In this regard, solely di(pivaloyloxy)iodobenzene [PhI(OPiv)2]-mediated oxidative C–H imidation by Wang et al. is
a mentionable work.[18] Here, the imidation
of 8-acylaminoquinolines and anilides by NFSI has been carried out
in tetrahydrofuran (THF) at 80 °C for 8 h under metal-free condition.
Very recently, our group reported an efficient method for a regioselective
(diacetoxy)iodobenzene (PIDA)-mediated oxidative amination of imidazopyridines
through C(sp2)–H functionalization leading to 3-amino-substitutedimidazopyridines.[4c] As a part of our ongoing
investigations on functionalization of imidazoheterocycles,[4] herein, we described a metal-free PIDA-mediated
regioselective imidation of imidazoheterocycles with NFSI (Scheme c).
Results and Discussion
2-Phenylimidazo[1,2-a]pyridine (1a) was initially selected as a model substrate with NFSI as an imidating
reagent (Table ).
At first, the reaction was carried out by taking 1a (0.2
mmol) with NFSI (1.0 equiv) at 60 °C in 1,2-DCE for 15 min. However,
no reaction took place, and both 1a and NFSI were recovered
(Table , entry 1).
To our delight, in the presence of 1 equiv of PIDA, the reaction afforded N-(2-phenylimidazo[1,2-a]pyridin-3-yl)-N-(phenylsulfonyl)benzenesulfonamide (2a) in
68% yield after 15 min (Table , entry 2). Further, the yield was not affected when the reaction
was carried out for 1 h. Other solvents, such as THF, CH3CN, toluene, 1,4-dioxane, ethanol, chlorobenzene, and dimethylformamide
(DMF), were also screened under the same conditions (Table , entries 3–9). Better
result was obtained in toluene affording 89% of the desired product
(Table , entry 5),
whereas very low yield of the desired product was formed with bis(trifluoroacetoxy)iodobenzene
(PIFA) (Table , entry
10). Next, we checked the effect of different oxidants such as K2S2O8, TBHP, and H2O2 instead of PIDA (Table , entries 11–13). In all cases, only trace amount of
imidated products were detected. The yield of the reaction was decreased
with diminished loading of PIDA to 0.5 equiv but remained unchanged
by increasing the amount to 1.5 equiv (Table , entries 14 and 15). No significant improvement
of the yield was found with increasing the reaction temperature, but
the yield was dropped when the reaction was carried out at 40 °C
(Table , entries 16
and 17). A trace amount of the desired product 2a were
obtained at room temperature (Table , entry 18). Direct imidation product of toulene was
not detected. Summing up, our study led to the following optimized
conditions: 1 equiv of PIDA in toluene at 60 °C for 15 min (Table , entry 5).
Table 1
Optimization for the Amination Reactiona
entry
oxidant (equiv)
solvent
yieldb (%)
1
1,2-DCE
0
2
PIDA (1)
1,2-DCE
68
3
PIDA (1)
THF
61
4
PIDA (1)
CH3CN
66
5
PIDA (1)
toluene
89
6
PIDA (1)
1,4-dioxane
78
7
PIDA (1)
EtOH
33
8
PIDA (1)
chlorobenzene
72
9
PIDA (1)
DMF
67
10
PIFA (1)
toluene
18
11
K2S2O8 (1)
toluene
trace
12
TBHP (1)
toluene
trace
13
H2O2 (1)
toluene
trace
14
PIDA (0.5)
toluene
41
15
PIDA (1.5)
toluene
90
16c
PIDA (1)
toluene
88
17d
PIDA (1)
toluene
59
18e
PIDA (1)
toluene
trace
Reaction conditions: 1a (0.2 mmol), NFSI (1.0 equiv), and oxidant (1.0 equiv) in
the presence
of solvent (1 mL) at 60 °C for 15 min.
Isolated yields.
Reaction was carried out at 80 °C.
Reaction was carried out at 40 °C.
Reaction was carried out at
rt.
Reaction conditions: 1a (0.2 mmol), NFSI (1.0 equiv), and oxidant (1.0 equiv) in
the presence
of solvent (1 mL) at 60 °C for 15 min.Isolated yields.Reaction was carried out at 80 °C.Reaction was carried out at 40 °C.Reaction was carried out at
rt.With the optimized reaction
conditions, we explored the substrate
scope of the present protocol, as shown in Scheme . A series of C-3 imidated imidazo[1,2-a]-pyridine products were obtained in good to excellent
yields (2a–2t). Imidazo[1,2-a]-pyridinescontaining electron-donating substituents such as −CH3 and −OCH3 at different positions of the
pyridine ring produced the desired products in excellent yields (2b–2d). Substrates possessing halogen substituents
attached to the six-membered ring successfully underwent the reaction
(2e–2f). 2-Phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine successfully reacted with NFSI to furnish the
desired product (2g). Next, we investigated the effect
of substituents at the phenyl ring at the C-2 position of imidazo[1,2-a]pyridine. The phenyl moiety containing both electron-donating
substituents and electron-withdrawing groups gave the corresponding
products in high yields (2h–2p). Hydroxy-containing
imidazo[1,2-a]pyridine was also tolerable for such
transformation (2q). Both naphthyl- and heteroaryl-substitutedimidazopyridines produced the desired products without any difficulties
(2r and 2s). The single-crystal X-ray diffraction
study of N-(phenylsulfonyl)-N-(2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)benzenesulfonamide (2s) was
performed to confirm the structure of imidated imidazopyridine.[19] Isopropyl-substituted (C-2) imidazo[1,2-a]pyridinecould also be successfully converted to the corresponding
product in excellent yield (2t). Moreover, no desired
imidated product was obtained when 3-phenylimidazo[1,2-a]pyridine (1u) was reacted with NFSI under the optimized
reaction conditions. This result suggests that the reaction selectively
took place at the C-3 position of imidazo[1,2-a]pyridine.
We also performed the reactions of 1b, 1e, and 1f with dibenzenesulfonimide [HN(SO2Ph)2] instead of NFSI under the same optimized conditions
(Scheme ). Here, the
corresponding products (2b, 2e, and 2f) were obtained in moderate yields. The gram-scale reaction
was also carried out under the normal laboratory setup by taking 2-phenylimidazo[1,2-a]pyridine (1a) and NFSI under the standard
reaction conditions on a 10 mmol scale. Gratifyingly, N-(2-phenylimidazo[1,2-a]pyridin-3-yl)-N-(phenylsulfonyl)benzenesulfonamide (2a) was obtained
without significant decrease in yield which clearly signifies the
practicability of our present protocol.
Scheme 2
Substrate Scope of
Imidazopyridinesa,b,c
Reaction conditions: 1 (0.2 mmol),
NFSI (1.0 equiv), and PIDA (1.0 equiv) in toluene (1 mL) at 60 °C
for 15 min.
10 mmol scale.
Reaction with HN(SO2Ph)2 instead of NFSI.
Substrate Scope of
Imidazopyridinesa,b,c
Reaction conditions: 1 (0.2 mmol),
NFSI (1.0 equiv), and PIDA (1.0 equiv) in toluene (1 mL) at 60 °C
for 15 min.10 mmol scale.Reaction with HN(SO2Ph)2 instead of NFSI.To extend
the generality of this methodology, we investigated the
present imidation reaction with other heterocycles such as imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazoles (Scheme ). Both 6-phenylimidazo[2,1-b]thiazole (3a) and 2-phenylbenzo[d]imidazo[2,1-b]thiazole (3b) reacted well to afford the
desired products in satisfactory yields (4a and 4b). 2-Phenylbenzo[d]imidazo[2,1-b]thiazolecontaining both electron-donating and electron-withdrawing
substituents underwent the reaction with NFSI without any difficulties
(4c–4e). Heteroaryl-substitutedbenzoimidazothiazole
was also effective for such transformation to afford the desired imidated
product in good yields (4f). However, 4,5-unsubstituted
imidazoles (3g and 3h) did not provide imidated
products under the optimized reaction conditions. The reactions of
imidazothiazole (3a) and benzoimidazothiazole (3b) with HN(SO2Ph)2 produced the desired
imidated products (4a and 4b) in lower yields
(Scheme ).
Scheme 3
Coupling
of Imidazothiazole and Benzoimidazothiazole with NFSIa,b
Reaction
conditions: 3 (0.2 mmol),
NFSI (1.0 equiv), and PIDA (1.0 equiv) in toluene (1 mL), at 60 °C
for 15 min.
Reaction with
HN(SO2Ph)2 instead of NFSI.
Coupling
of Imidazothiazole and Benzoimidazothiazole with NFSIa,b
Reaction
conditions: 3 (0.2 mmol),
NFSI (1.0 equiv), and PIDA (1.0 equiv) in toluene (1 mL), at 60 °C
for 15 min.Reaction with
HN(SO2Ph)2 instead of NFSI.The current methodology is also applicable for N-substituted indole
and indolizine derivatives (Figure ). Both N-methylindole and 1-methyl-2-phenyl
indole produced the desired products in high yields (5a and 5b). Moreover, indolizine derivatives smoothly
participated in this reaction to give the desired imidated products
in good yields (6a and 6b).
Figure 1
Substrate scope with
other heterocycles. Reaction conditions: N-substituted
indoles or indolizines (0.2 mmol), NFSI (1.0 equiv), and PIDA (1.0
equiv) in toluene (1 mL) at 60 °C for 15 min.
Substrate scope with
other heterocycles. Reaction conditions: N-substitutedindoles or indolizines (0.2 mmol), NFSI (1.0 equiv), and PIDA (1.0
equiv) in toluene (1 mL) at 60 °C for 15 min.Amino derivative of imidazopyridine (7a) could be
easily synthesized from N-(2 phenylimidazo[1,2-a]pyridin-3-yl)-N-(phenylsulfonyl)benzenesulfonamide
(2a) using TfOH (Scheme ).[14b]
Scheme 4
Synthetic Utility
To acquire the mechanistic
insights into the reaction pathway,
few control experiments were carried out (Scheme ). It was found that imidazo[1,2-a]pyridine failed to give the corresponding product in the
presence radical scavengers such as 2,2,6,6-tetramethylpiperidine-1-oxyl,
2,6-di-tert-butyl-4-methylphenol, and p-benzoquinone (Scheme a). The use of a stoichiometric amount of 1,1-diphenylethylene was
also completely suppressed the imidation reaction. Moreover, N-(2,2-diphenylvinyl)-N-(phenylsulfonyl)benzenesulfonamide
(8a) was obtained in 53% yield along with almost full
recovery of 1a (Scheme b). These observations imply that the reaction proceeds
through a radical pathway.
Scheme 5
Control Experiments
On the basis of the control experiments (Scheme ) as well as previous reports,[4c,18,20] a plausible mechanism of PIDA-mediated
C–H imidation of imidazopyridines with NFSI is presented in Scheme . Probably, the first
step is the PIDA-mediated oxidation of imidazopyridine (1a) to imidazopyridine radicalcation (A) along with the
formation of radical (B) through a single electron-transfer
process. After that the radical (B) is oxidized by NFSI
via one-electron F-atom transfer pathway, affording the bis-sulfonylamidyl
radical (C). On the other hand, dibenzenesulfonimide
[HN(SO2Ph)2] could also produce N-iodoamido species (D) in the presence of PIDA which
subsequently gives bis-sulfonylamidyl radical (C) and
generates imidazopyridine radicalcation (A) from 1a. Finally, the resulting imidazopyridine radicalcation
(A) regioselectively coupled with the bis-sulfonylamidyl
radical (C) to produce the imidazolenium ion (E) which consequently affords the product (2a) through
the elimination of AcOH.
Scheme 6
Plausible Mechanistic Pathway
Conclusions
In
summary, we have developed an efficient and simple methodology
for PIDA-mediated regioselective imidation of imidazo[1,2-a]pyridines using NFSI as the nitrogen source under metal-free
conditions in short reaction times. The present methodology is also
applicable to other heterocycles such as imidazo[2,1-b]thiazole, benzo[d]imidazo-[2,1-b]thiazole, indole, and indolizine derivatives. Metal-free conditions,
broad substrates scope, fast reactions, and gram-scale synthesis are
the notable advantages of our methodology. To the best of our knowledge,
this is the first report of metal-free imidation of imidazoheterocycles
using NFSI featuring the incorporation of −N(SO2Ph)2 group. We believe that our present protocol will
open a new possibility for the forthcoming more practical and selective
C–N bond formation route of heterocycles under metal-free conditions.
Experimental
Section
General Information
All reagents were purchased from
commercial sources and used without further purification. 1H NMR spectra were determined on a 400 MHz spectrometer as solutions
in CDCl3. Chemical shifts are expressed in parts per million
(δ), and the signals were reported as s (singlet), d (doublet),
t (triplet), m (multiplet), dd (double of doublet), and coupling constants
(J) were given in hertz. 13C{1H} NMR spectra were recorded at 100 MHz in CDCl3 solution.
Chemical shifts as an internal standard are referenced to CDCl3 (δ = 7.26 for 1H and δ = 77.16 for 13C{1H} NMR) as an internal standard. Thin-layer
chromatography (TLC) was done on a silica gel-coated glass slide.
All solvents were dried and distilled before use. Commercially available
solvents were freshly distilled before the reaction. All reactions
involving moisture sensitive reactants were executed using an oven-dried
glassware. X-ray single crystal data were collected using Mo Kα
(λ = 0.71073 Å) radiation with a CCD area detector. Melting
points were determined on a glass disk with an electrical bath and
are uncorrected. All of the imidazoheterocycles were prepared by our
reported method.[4b,4d]
General Experimental Procedures
for the Synthesis of 2a–2t and 4a–4f
Imidazoheterocycles (0.2
mmol), NFSI (1.0 equiv, 63 mg), and PIDA (1.0 equiv, 65 mg) were taken
in an oven-dried reaction vessel equipped with a magnetic stir bar.
Then, toluene (1 mL) was added and stirred at 60 °C for 15 min.
The progress of the reaction was monitored by TLC. After completion,
the reaction mixture was diluted with 8 mL of water/ethyl acetate
(1:1). Then, the reaction mixture was extracted with ethyl acetate,
and the organic phase was dried over anhydrous Na2SO4. After evaporating the solvent under reduced pressure, the
crude residue was obtained. Finally, it was purified by column chromatography
on silica gel (60–120 mesh) using petroleum ether/ethylacetate
as an eluent to afford the pure imidated products (2a–2t and 4a–4f).
Scheme 1
Scheme 2
Scheme 3
Figure 1
Scheme 4
Scheme 5
Scheme 6